NF-κB, ERK, p38 MAPK and JNK contribute to the initiation and/or maintenance of mechanical allodynia induced by tumor necrosis factor-alpha in the red nucleus

Abstract

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays facilitated roles in the development of abnormal pain. Here, the roles of nuclear factor-kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) in TNF-α-evoked mechanical allodynia were investigated. Repeated microinjection of recombinant rat TNF-α (20 ng daily for 3 days) into the unilateral RN of normal rats induced a significant mechanical allodynia in the contralateral but not ipsilateral hind paw at the fifth day and disappeared 24h later. Re-injection of a single bolus of 20 ng TNF-α into the same RN reproduced this mechanical allodynia within 30 min, which was used as a pain model for further experiments. Immunohistochemistry demonstrated that NF-κB, phospho-ERK (p-ERK) and p-p38 MAPK in the RN were significantly up-regulated at 1h after TNF-α microinjection, the up-regulations of NF-κB and p-ERK but not p-p38 MAPK remained at high levels till 4h later. A significant up-regulation of p-JNK occurred at 4h (but not 1h) after TNF-α microinjection, which was later than those of NF-κB, p-ERK and p-p38 MAPK. Pre-treatment with NF-κB inhibitor PDTC, ERK inhibitor PD98059 or p38 MAPK inhibitor SB203580 at 30 min before TNF-α microinjected into the RN completely prevented TNF-α-evoked mechanical allodynia. Pre-treatment with JNK inhibitor SP600125 did not prevent but reversed TNF-α-evoked mechanical allodynia during the subsequent detection time. Post-treatment with PDTC, PD98059 or SP600125 (but not SB203580) at 4h after TNF-α microinjected into the RN significantly reversed TNF-α-evoked mechanical allodynia. These results further prove that TNF-α in the RN plays a crucial role in the development of abnormal pain, and the algesic effect of TNF-α is initiated through activating NF-κB, ERK and p38 MAPK. The later maintenance of TNF-α-evoked mechanical allodynia mainly relies on the activation of NF-κB, ERK and JNK, but not p38 MAPK.

Keywords: DRG; ERK; IL; JNK; LTP; Mitogen-activated protein kinase; NF-κB; NGF; Nuclear factor-kappa B; PDTC; PWT; RN; RVM; Rat; Red nucleus; SNI; TNF-α; Tumor necrosis factor-alpha; c-Jun N-terminal kinase; dorsal root ganglia; extracellular signal-regulated kinase; interleukin; long-term potentiation; nerve growth factor; nuclear factor-kappa B; p38 MAPK; p38 mitogen-activated protein kinase; paw withdrawal threshold; pyrrolidine dithiocarbamate; red nucleus; rostral ventromedial medulla; spared nerve injury; tumor necrosis factor-alpha.